EXPAREL- bupivacaine injection, suspens ion, liposomal Pacira Pharmaceuticals Inc.----------

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use EXPAREL safely and effectively. See fullprescribing information for EXPAREL.

EXPAREL (bupivacaine liposome injectable suspension) Initial U.S. Approval: 1972

RECENT MAJOR CHANGESIndications and Usage (1) (04/2018)Dosage and Administration (2.1, 2.2, 2.3) (04/2018)Warnings and Precautions (5.2) (04/2018)

INDICATIONS AND USAGEEXPAREL is indicated for single-dose infiltration in adults to produce postsurgical local analgesia and as an interscalenebrachial plexus nerve block to produce postsurgical regional analgesia (1).

Limitations of Use Safety and efficacy have not been established in other nerve blocks

DOSAGE AND ADMINISTRATIONEXPAREL is intended for single-dose administration only (2.1).Different formulations of bupivacaine are not bioequivalent even if the milligram strength is the same. It is not possibleto convert dosing from other formulations of bupivacaine to EXPAREL (2.1, 2.5).DO NOT dilute EXPAREL with water for injection or other hypotonic solutions (2.1).The recommended dose of EXPAREL for local infiltration in adults is up to a maximum dose of 266 mg (20 mL). SeeFull Prescribing Information for guidance on dose selection (2.2).The recommended dose of EXPAREL for interscalene brachial plexus nerve block in adults is 133 mg (10 mL) (2.2).See Full Prescribing Information for important injection instructions and compatibility considerations (2.3, 2.4).

DOSAGE FORMS AND STRENGTHSInjectable suspension: 266 mg/20 mL (13.3 mg/mL) single-dose vial (3) 133 mg/10 mL (13.3 mg/mL) single-dose vial (3)

CONTRAINDICATIONSEXPAREL is contraindicated in obstetrical paracervical block anesthesia (4).

WARNINGS AND PRECAUTIONSMonitor cardiovascular status, neurological status, and vital signs during and after injection of EXPAREL (5.1).Because amide-type local anesthetics, such as bupivacaine, are metabolized by the liver, use EXPAREL cautiously inpatients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize localanesthetics normally, are at a greater risk of developing toxic plasma concentrations (5.1).Avoid additional use of local anesthetics within 96 hours following administration of EXPAREL (5.2).

ADVERSE REACTIONSAdverse reactions reported with an incidence greater than or equal to 10% following EXPAREL administration viainfiltration were nausea, constipation, and vomiting (6.1).Adverse reactions reported with an incidence greater than or equal to 10% following EXPAREL administration via nerveblock were nausea, pyrexia, and constipation (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Pacira Pharmaceuticals, Inc. at 1-855-RX-EXPAREL (1-855-793-9727) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONSLidocaine or other non-bupivacaine local anesthetics: Do not admix with EXPAREL. EXPAREL may be administered atleast 20 minutes or more following local administration of lidocaine (7).Bupivacaine HCl: Do not exceed a milligram dose of bupivacaine HCl solution to EXPAREL of 1:2 when admixing, as thismay impact the pharmacokinetics and/or physicochemical properties of the drugs (7).Do not dilute EXPAREL with water or other hypotonic agents, as it will result in disruption of the liposomal particles (7).

USE IN SPECIFIC POPULATIONS

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USE IN SPECIFIC POPULATIONSPregnancy: May cause fetal harm (8.1).

See 17 for PATIENT COUNSELING INFORMATION.Revised: 4 /2018

FULL PRESCRIBING INFORMATION: CONTENTS*1. INDICATIONS AND USAGE2. DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Information2.2 Recommended Dosing in Adults2.3 Injection Instructions2.4 Compatibility Considerations2.5 Non-Interchangeability with Other Formulations of Bupivacaine

3. DOSAGE FORMS AND STRENGTHS4. CONTRAINDICATIONS5. WARNINGS AND PRECAUTIONS

5.1 Warnings and Precautions for Bupivacaine Containing Products5.2 Warnings and Precautions Specific for EXPAREL

6. ADVERSE REACTIONS6.1 Clinical Trials6.2 Postmarketing Experience

7. DRUG INTERACTIONS8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy8.2 Lactation8.4 Pediatric Use8.5 Geriatric Use8.6 Hepatic Impairment8.7 Renal Impairment

10. OVERDOSAGE11. DESCRIPTION12. CLINICAL PHARMACOLOGY

12.1 Mechanism of Action12.2 Pharmacodynamics12.3 Pharmacokinetics

13. NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14. CLINICAL STUDIES14.1 Studies Confirming Efficacy14.2 Studies That Do Not Support an Indication in Nerve Block

16. HOW SUPPLIED/STORAGE AND HANDLING17. PATIENT COUNSELING INFORMATION*

FULL PRESCRIBING INFORMATION

1. INDICATIONS AND USAGEEXPAREL is indicated for single-dose infiltration in adults to produce postsurgical local analgesia andas an interscalene brachial plexus nerve block to produce postsurgical regional analgesia.

Limitations of Use

Sections or subsections omitted from the full prescribing information are not listed.

Safety and efficacy h not been established in other nerve blocks.

2. DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Adminis tration InformationEXPAREL is intended for single-dose administration only.Different formulations of bupivacaine are not bioequivalent even if the milligram strength is thesame. Therefore, it is not possible to convert dosing from any other formulations of bupivacaine toEXPAREL [see Dosage and Administration (2.5)].DO NOT dilute EXPAREL with water for injection or other hypotonic agents, as it will result indisruption of the liposomal particles.Use suspensions of EXPAREL diluted with preservative-free normal (0.9%) saline for injection orlactated Ringer’s solution within 4 hours of preparation in a syringe.Do not administer EXPAREL if it is suspected that the vial has been frozen or exposed to hightemperature (greater than 40°C or 104°F) for an extended period.Inspect EXPAREL visually for particulate matter and discoloration prior to administration,whenever solution and container permit. Do not administer EXPAREL if the product is discolored.

2.2 Recommended Dos ing in AdultsLocal Analgesia via Infiltration

The recommended dose of EXPAREL for local infiltration in adults is up to a maximum dose of 266 mg(20 mL), and is based on the following factors:

Size of the surgical siteVolume required to cover the areaIndividual patient factors that may impact the safety of an amide local anesthetic

As general guidance in selecting the proper dosing, two examples of infiltration dosing are provided:In patients undergoing bunionectomy, a total of 106 mg (8 mL) of EXPAREL was administered, with7 mL infiltrated into the tissues surrounding the osteotomy, and 1 mL infiltrated into thesubcutaneous tissue.In patients undergoing hemorrhoidectomy, a total of 266 mg (20 mL) of EXPAREL was diluted with10 mL of saline, for a total of 30 mL, divided into six 5 mL aliquots, injected by visualizing the analsphincter as a clock face and slowly infiltrating one aliquot to each of the even numbers to producea field block.

Regional Analgesia via Interscalene Brachial Plexus Nerve Block

The recommended dose of EXPAREL for interscalene brachial plexus nerve block in adults is 133 mg(10 mL), and is based upon one study of patients undergoing either total shoulder arthroplasty or rotatorcuff repair.

2.3 Injection Ins tructionsEXPAREL should be injected slowly (generally 1 to 2 mL per injection) with frequent aspiration tocheck for blood and minimize the risk of inadvertent intravascular injection. Do not exceed a maximumdosage of 266 mg (20 mL, 1.3% of undiluted drug) for infiltration and 133 mg (10 mL) for interscalenebrachial plexus nerve block.

Administer EXPAREL undiluted or diluted to increase volume up to a final concentration of 0.89mg/mL (i.e., 1:14 dilution by volume) with normal (0.9%) saline or lactated Ringer’s solution.Invert vials of EXPAREL multiple times to re-suspend the particles immediately prior to withdrawalfrom the vial.Administer EXPAREL with a 25 gauge or larger bore needle to maintain the structural integrity ofthe liposomal bupivacaine particles.

2.4 Compatibility Cons iderationsSome physicochemical incompatibilities exist between EXPAREL and certain other drugs. Directcontact of EXPAREL with these drugs results in a rapid increase in free (unencapsulated) bupivacaine,

altering EXPAREL characteristics and potentially affecting the safety and efficacy of EXPAREL.Therefore, admixing EXPAREL with other drugs prior to administration is not recommended [See DrugInteractions (7)].

Non-bupivacaine based local anesthetics, including lidocaine, may cause an immediate release ofbupivacaine from EXPAREL if administered together locally. The administration of EXPAREL mayfollow the administration of lidocaine after a delay of 20 minutes or more.Bupivacaine HCl administered together with EXPAREL may impact the pharmacokinetic and/orphysicochemical properties of EXPAREL, and this effect is concentration dependent. Therefore,bupivacaine HCl and EXPAREL may be administered simultaneously in the same syringe, andbupivacaine HCl may be injected immediately before EXPAREL as long as the ratio of themilligram dose of bupivacaine HCl solution to EXPAREL does not exceed 1:2. The toxic effects of these drugs are additive and their administration should be used with cautionincluding monitoring for neurologic and cardiovascular effects related to local anesthetic systemictoxicity [See Warnings and Precautions (5.1) and Overdosage (10)].When a topical antiseptic such as povidone iodine (e.g., Betadine ) is applied, the site should beallowed to dry before EXPAREL is administered into the site. EXPAREL should not be allowed tocome into contact with antiseptics such as povidone iodine in solution.

Studies conducted with EXPAREL demonstrated that the most common implantable materials(polypropylene, PTFE, silicone, stainless steel, and titanium) are not affected by the presence ofEXPAREL any more than they are by saline. None of the materials studied had an adverse effect onEXPAREL.

When administered in recommended doses and concentrations, bupivacaine HCl does not ordinarilyproduce irritation or tissue damage and does not cause methemoglobinemia.

2.5 Non-Interchangeability with Other Formulations of BupivacaineDifferent formulations of bupivacaine are not bioequivalent even if the milligram dosage is the same.Therefore, it is not possible to convert dosing from any other formulations of bupivacaine toEXPAREL and vice versa.

Liposomal encapsulation or incorporation in a lipid complex can substantially affect a drug’s functionalproperties relative to those of the unencapsulated or nonlipid-associated drug. In addition, differentliposomal or lipid-complexed products with a common active ingredient may vary from one another inthe chemical composition and physical form of the lipid component. Such differences may affectfunctional properties of these drug products. Do not substitute.

3. DOSAGE FORMS AND STRENGTHSEXPAREL (bupivacaine liposome injectable suspension) is a white to off-white, milky aqueoussuspension that is available in the following vial sizes:

266 mg/20 mL (13.3 mg/mL) single-dose vial133 mg/10 mL (13.3 mg/mL) single-dose vial

4. CONTRAINDICATIONSEXPAREL is contraindicated in obstetrical paracervical block anesthesia. While EXPAREL has notbeen tested with this technique, the use of bupivacaine HCl with this technique has resulted in fetalbradycardia and death.

5. WARNINGS AND PRECAUTIONS

5.1 Warnings and Precautions for Bupivacaine Containing ProductsThe safety and effectiveness of bupivacaine and other amide-containing products depend on properdosage, correct technique, adequate precautions, and readiness for emergencies. As there is a potentialrisk of severe life-threatening adverse effects associated with the administration of bupivacaine, anybupivacaine-containing product should be administered in a setting where trained personnel andequipment are available to promptly treat patients who show evidence of neurological or cardiac

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toxicity [See Overdosage (10)].

Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signsand the patient’s state of consciousness should be performed after injection of bupivacaine and otheramide-containing products. Restlessness, anxiety, incoherent speech, lightheadedness, numbness andtingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching,depression, or drowsiness may be early warning signs of central nervous system toxicity.

Bupivacaine and other amide-containing products should also be used with caution in patients withimpaired cardiovascular function because they may be less able to compensate for functional changesassociated with the prolongation of AV conduction produced by these drugs.

Injection of multiple doses of bupivacaine and other amide-containing products may cause significantincreases in plasma concentrations with each repeated dose due to slow accumulation of the drug or itsmetabolites, or to slow metabolic degradation. Tolerance to elevated blood concentrations varies withthe status of the patient.

Because amide-type local anesthetics, such as bupivacaine, are metabolized by the liver, these drugsshould be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, becauseof their inability to metabolize local anesthetics normally, are at a greater risk of developing toxicplasma concentrations.

Central Nervous System Reactions

The incidences of adverse neurologic reactions associated with the use of local anesthetics may berelated to the total dose of local anesthetic administered and are also dependent upon the particular drugused, the route of administration, and the physical status of the patient. Many of these effects may berelated to local anesthetic techniques, with or without a contribution from the drug. Neurologic effectsfollowing infiltration of soft tissue may include persistent anesthesia, paresthesia, weakness, andparalysis, all of which may have slow, incomplete, or no recovery.

Central nervous system reactions are characterized by excitation and/or depression. Restlessness,anxiety, dizziness, tinnitus, blurred vision, or tremors may occur, possibly proceeding to convulsions.However, excitement may be transient or absent, with depression being the first manifestation of anadverse reaction. This may quickly be followed by drowsiness merging into unconsciousness andrespiratory arrest. Other central nervous system effects may be nausea, vomiting, chills, and constrictionof the pupils. The incidence of convulsions associated with the use of local anesthetics varies with theprocedure used and the total dose administered.

Cardiovascular System Reactions

Toxic blood concentrations depress cardiac conductivity and excitability, which may lead toatrioventricular block, ventricular arrhythmias, and cardiac arrest, sometimes resulting in fatalities. Inaddition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreasedcardiac output and arterial blood pressure [See Warnings and Precautions (5.1) and Overdosage (10)].

Allergic Reactions

Allergic-type reactions are rare and may occur as a result of hypersensitivity to the local anesthetic orto other formulation ingredients. These reactions are characterized by signs such as urticaria, pruritus,erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting,dizziness, syncope, excessive sweating, elevated temperature, and possibly anaphylactoid-likesymptoms (including severe hypotension). Cross-sensitivity among members of the amide-type localanesthetic group has been reported. The usefulness of screening for sensitivity has not beendefinitively established.

Chondrolysis

Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is anunapproved use, and there have been postmarketing reports of chondrolysis in patients receiving suchinfusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases ofgleno-humeral chondrolysis have been described in pediatric patients and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours.There is insufficient information to determine whether shorter infusion periods are not associated withthese findings. The time of onset of symptoms, such as joint pain, stiffness, and loss of motion can be

variable, but may begin as early as the second month after surgery. Currently, there is no effectivetreatment for chondrolysis; patients who have experienced chondrolysis have required additionaldiagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement.

5.2 Warnings and Precautions Specific for EXPARELAs there is a potential risk of severe life-threatening adverse effects associated with the administrationof bupivacaine, EXPAREL should be administered in a setting where trained personnel and equipmentare available to promptly treat patients who show evidence of neurological or cardiac toxicity [SeeOverdosage (10)].

Caution should be taken to avoid accidental intravascular injection of EXPAREL. Convulsions andcardiac arrest have occurred following accidental intravascular injection of bupivacaine and otheramide-containing products.

Avoid additional use of local anesthetics within 96 hours following administration of EXPAREL [SeeDosage and Administration (2.4) and Clinical Pharmacology (12.3)].

EXPAREL has not been evaluated for the following uses and, therefore, is not recommended for thesetypes of analgesia or routes of administration.

epiduralintrathecalregional nerve blocks other than interscalene brachial plexus nerve blockintravascular or intra-articular use

EXPAREL has not been evaluated for use in the following patient populations and, therefore, is notrecommended for administration to these groups.

patients younger than 18 years oldpregnant patients

The potential sensory and/or motor loss with EXPAREL is temporary and varies in degree and durationdepending on the site of injection and dosage administered and may last for up to 5 days as seen inclinical trials.

6. ADVERSE REACTIONSThe following serious adverse reactions have been associated with bupivacaine hydrochloride inclinical trials and are described in greater detail in other sections of the labeling:

Central Nervous System Reactions [see Warnings and Precautions (5.1)]Cardiovascular System Reactions [see Warnings and Precautions (5.1)]Allergic Reactions [see Warnings and Precautions (5.1)]Chondrolysis [see Warnings and Precautions (5.1)]Accidental intravascular injection [see Warnings and Precautions (5.2)]

6.1 Clinical TrialsAdverse Reactions Reported in All Local Infiltration Clinical Studies

Because clinical studies are conducted under widely varying conditions, adverse reaction ratesobserved in the clinical trials of a drug cannot be directly compared to rates in the clinical studies ofanother drug and may not reflect the rates observed in practice.

The safety of EXPAREL was evaluated in 10 randomized, double-blind, local administration into thesurgical site clinical studies involving 823 patients undergoing various surgical procedures. Patientswere administered a dose ranging from 66 to 532 mg of EXPAREL. In these studies, the most commonadverse reactions (incidence greater than or equal to 10%) following EXPAREL administration werenausea, constipation, and vomiting.

The common adverse reactions (incidence greater than or equal to 2% to less than 10%) followingEXPAREL administration were pyrexia, dizziness, edema peripheral, anemia, hypotension, pruritus,tachycardia, headache, insomnia, anemia postoperative, muscle spasms, hemorrhagic anemia, back pain,somnolence, and procedural pain.

The less common/rare adverse reactions (incidence less than 2%) following EXPAREL administrationwere chills, erythema, bradycardia, anxiety, urinary retention, pain, edema, tremor, dizziness postural,paresthesia, syncope, incision site edema, procedural hypertension, procedural hypotension, proceduralnausea, muscular weakness, neck pain, pruritus generalized, rash pruritic, hyperhidrosis, cold sweat,urticaria, palpitations, sinus bradycardia, supraventricular extrasystoles, ventricular extrasystoles,ventricular tachycardia, hypertension, pallor, anxiety, confusional state, depression, agitation,restlessness, hypoxia, laryngospasm, apnea, respiratory depression, respiratory failure, bodytemperature increased, blood pressure increased, blood pressure decreased, oxygen saturationdecreased, urinary incontinence, vision blurred, tinnitus, drug hypersensitivity, and hypersensitivity.

Neurological and Cardiac Adverse Reactions

In the EXPAREL surgical site infiltration studies, adverse reactions with an incidence greater than orequal to 1% in the Nervous System Disorders system organ class following EXPAREL administrationwere dizziness (6.2%), headache (3.8%), somnolence (2.1%), hypoesthesia (1.5%), and lethargy (1.3%).The adverse reactions with an incidence greater than or equal to 1% in the Cardiac Disorders systemorgan class following EXPAREL administration were tachycardia (3.9%) and bradycardia (1.6%).

Adverse Reactions Reported in All Local Infiltration Placebo-Controlled Trials

Adverse reactions with an incidence greater than or equal to 2% reported by patients in clinical studiescomparing 8 mL EXPAREL 1.3% (106 mg) to placebo and 20 mL EXPAREL 1.3% (266 mg) to placeboare shown in Table 1.

Table 1: Treatment-Emergent Adverse Reactions (TEAE) with an Incidence Greater than or Equal to 2%:Local Infiltration Placebo-Controlled Studies

STUDY 1 STUDY 2

EXPAREL Placebo EXPAREL Placebo

System Organ Class Preferred Term

8 mL/1.3% (106 mg) (N=97) n (%)

(N=96) n (%)

20 mL/1.3% (266 mg) (N=95) n (%)

(N=94) n (%)

Any TEAE 53 (54.6) 59 (61.5) 10 (10.5) 17 (18.1)

Gastrointestinal Disorders 41 (42.3) 38 (39.6) 7 (7.4) 13 (13.8) Nausea 39 (40.2) 36 (37.5) 2 (2.1) 1 (1.1) Vomiting 27 (27.8) 17 (17.7) 2 (2.1) 4 (4.3) Constipation 2 (2.1) 1 (1.0) 2 (2.1) 2 (2.1) Anal Hemorrhage 0 (0.0) 0 (0.0) 3 (3.2) 4 (4.3) Painful Defecation 0 (0.0) 0 (0.0) 2 (2.1) 5 (5.3) Rectal Discharge 0 (0.0) 0 (0.0) 1 (1.1) 3 (3.2)

Nervous System Disorders 20 (20.6) 30 (31.3) 0 (0.0) 0 (0.0) Dizziness 11 (11.3) 25 (26.0) 0 (0.0) 0 (0.0) Headache 5 (5.2) 8 (8.3) 0 (0.0) 0 (0.0) Somnolence 5 (5.2) 1 (1.0) 0 (0.0) 0 (0.0) Syncope 2 (2.1) 0 (0.0) 0 (0.0) 0 (0.0)

Skin And Subcutaneous Tissue Disorders 8 (8.2) 7 (7.3) 0 (0.0) 0 (0.0) Pruritus Generalized 5 (5.2) 6 (6.3) 0 (0.0) 0 (0.0) Pruritus 3 (3.1) 1 (1.0) 0 (0.0) 0 (0.0)

a b

Study 1: Bunionectomy Study 2: Hemorrhoidectomy

At each level of summation (overall, system organ class, preferred term), patients are only counted once.Preferred terms are included where at least 2% of patients reported the event in any treatment group.TEAE = treatment-emergent adverse event.

Investigations 5 (5.2) 3 (3.1) 4 (4.2) 3 (3.2) Alanine Aminotransferase Increased 3 (3.1) 3 (3.1) 1 (1.1) 0 (0.0) Aspartate Aminotransferase Increased 3 (3.1) 2 (2.1) 0 (0.0) 0 (0.0) Blood Creatinine Increased 2 (2.1) 0 (0.0) 0 (0.0) 0 (0.0) Body Temperature Increased 0 (0.0) 0 (0.0) 3 (3.2) 3 (3.2)

General Disorders And Administration SiteConditions

4 (4.1) 0 (0.0) 1 (1.1) 1 (1.1)

Feeling Hot 2 (2.1) 0 (0.0) 0 (0.0) 0 (0.0) Pyrexia 2 (2.1) 0 (0.0) 1 (1.1) 1 (1.1)

Infections And Infestations 2 (2.1) 1 (1.0) 0 (0.0) 0 (0.0) Fungal Infection 2 (2.1) 1 (1.0) 0 (0.0) 0 (0.0)

Injury, Poisoning And ProceduralComplications

2 (2.1) 0 (0.0) 0 (0.0) 0 (0.0)

Post Procedural Swelling 2 (2.1) 0 (0.0) 0 (0.0) 0 (0.0)

Metabolism And Nutrition Disorders 2 (2.1) 2 (2.1) 0 (0.0) 0 (0.0) Decreased Appetite 2 (2.1) 2 (2.1) 0 (0.0) 0 (0.0)

Adverse Reactions Reported in All Nerve Block Clinical Studies

The safety of EXPAREL was evaluated in four randomized, double-blind, placebo-controlled nerveblock clinical studies involving 469 patients undergoing various surgical procedures. Patients wereadministered a dose of either 133 or 266 mg of EXPAREL. In these studies, the most common adversereactions (incidence greater than or equal to 10%) following EXPAREL administration were nausea,pyrexia, and constipation.

The common adverse reactions (incidence greater than or equal to 2% to less than 10%) followingEXPAREL administration as a nerve block were muscle twitching, dysgeusia, urinary retention, fatigue,headache, confusional state, hypotension, hypertension, hypoesthesia oral, pruritus generalized,hyperhidrosis, tachycardia, sinus tachycardia, anxiety, fall, body temperature increased, edemaperipheral, sensory loss, hepatic enzyme increased, hiccups, hypoxia, and post-procedural hematoma.

The less common/rare adverse reactions (incidence less than 2%) following EXPAREL administrationas a nerve block were arrhythmia, atrial fibrillation, atrioventricular block first degree, bradycardia,bundle branch block left, bundle branch block right, cardiac arrest, hearing impaired, vision blurred,visual impairment, asthenia, chills, hyperthermia, cellulitis, lung infection, pneumonia, proceduralnausea, wound dehiscence, wound secretion, electrocardiogram QT prolonged, white blood cell countincreased, arthralgia, back pain, joint swelling, mobility decreased, muscle spasms, muscular weakness,musculoskeletal pain, paraesthesia, presyncope, sedation, somnolence, syncope, delirium, dysuria,urinary incontinence, atelectasis, cough, dyspnea, lung infiltration, blister, drug eruption, erythema, rash,urticaria, deep vein thrombosis, hematoma, and orthostatic hypotension.

Adverse reactions with an incidence greater than or equal to 2% reported by patients in clinical studiescomparing 10 mL EXPAREL 1.3% (133 mg) and 20 mL EXPAREL 1.3% (266 mg) to placebo areshown in Table 2.

Neurological and Cardiac Adverse Reactions

In the EXPAREL nerve block studies, adverse reactions with an incidence greater than or equal to 1% inthe Nervous System Disorders system organ class following EXPAREL administration were motor

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dysfunction (14.9%), dysgeusia (7.2%), headache (5.1%), hypoesthesia (2.3%), and sensory loss (2.3%).The adverse reactions with an incidence greater than or equal to 1% in the Cardiac Disorders systemorgan class following EXPAREL administration were tachycardia (3.0%), sinus tachycardia (2.3%), andbradycardia (1.3%).

Table 2: Treatment-Emergent Adverse Reactions with an Incidence Greater than or Equal to 2%: NerveBlock Placebo-Controlled Studies

SYSTEM ORGAN CLASS Preferred Term

133 mg (N=168)

n (%)

266 mg (N=301)

n (%)

Placebo (N=357)

n (%)

Number of Subjects with at Least One TEAE 152 (90.5) 260 (86.4) 299 (83.8)

Blood and Lymphatic System Disorders 2 (1.2) 22 (7.3) 15 (4.2) Anemia 2 (1.2) 18 (6.0) 13 (3.6)

Cardiac Disorders 13 (7.7) 34 (11.3) 38 (10.6) Atrial Fibrillation 1 (0.6) 4 (1.3) 8 (2.2) Sinus Tachycardia 3 (1.8) 8 (2.7) 4 (1.1) Tachycardia 3 (1.8) 11 (3.7) 10 (2.8)

Gastrointestinal Disorders 84 (50.0) 154 (51.2) 184 (51.5) Constipation 29 (17.3) 66 (21.9) 68 (19.0) Dyspepsia 3 (1.8) 7 (2.3) 7 (2.0) Hypoesthesia Oral 6 (3.6) 8 (2.7) 7 (2.0) Nausea 62 (36.9) 111 (36.9) 133 (37.3) Vomiting 17 (10.1) 55 (18.3) 73 (20.4)

General Disorders And Administration SiteConditions

52 (31.0) 102 (33.9) 91 (25.5)

Fatigue 7 (4.2) 15 (5.0) 15 (4.2) Feeling Cold 0 10 (3.3) 8 (2.2) Edema Peripheral 4 (2.4) 6 (2.0) 8 (2.2) Peripheral Swelling 3 (1.8) 8 (2.7) 4 (1.1) Pyrexia 36 (21.4) 70 (23.3) 64 (17.9)

Injury, Poisoning And ProceduralComplications

18 (10.7) 44 (14.6) 32 (9.0)

Anemia Postoperative 0 8 (2.7) 10 (2.8) Contusion 4 (2.4) 1 (0.3) 0 Fall 4 (2.4) 8 (2.7) 1 (0.3) Post Procedural Hematoma 4 (2.4) 1 (0.3) 0 Procedural Hypotension 2 (1.2) 13 (4.3) 7 (2.0)

Investigations 18 (10.7) 31 (10.3) 31 (8.7) Body Temperature Increased 1 (0.6) 10 (3.3) 4 (1.1) Hepatic Enzyme Increased 7 (4.2) 1 (0.3) 3 (0.8)

Metabolism and Nutrition Disorders 13 (7.7) 18 (6.0) 25 (7.0) Hypokalemia 7 (4.2) 9 (3.0) 14 (3.9)

Musculoskeletal And Connective TissueDisorders

22 (13.1) 47 (15.6) 41 (11.5)

At each level of summation (overall, system organ class, preferred term), patients are only counted once.Preferred terms are included where at least 2% of patients reported the event in any treatment group.TEAE = treatment-emergent adverse event.

Mobility Decreased 0 6 (2.0) 5 (1.4) Muscle Twitching 14 (8.3) 21 (7.0) 25 (7.0)

Nervous System Disorders 72 (42.9) 101 (33.6) 112 (31.4) Dizziness 8 (4.8) 28 (9.3) 40 (11.2) Dysgeusia 12 (7.1) 22 (7.3) 21 (5.9) Headache 14 (8.3) 10 (3.3) 10 (2.8) Hypoesthesia 6 (3.6) 5 (1.7) 2 (0.6) Motor Dysfunction 35 (20.8) 35 (11.6) 37 (10.4) Sensory Loss 4 (2.4) 7 (2.3) 1 (0.3)

Psychiatric Disorders 10 (6.0) 33 (11.0) 44 (12.3) Anxiety 3 (1.8) 9 (3.0) 6 (1.7) Confusional State 3 (1.8) 15 (5.0) 14 (3.9) Insomnia 5 (3.0) 10 (3.3) 19 (5.3)

Renal And Urinary Disorders 9 (5.4) 31 (10.3) 31 (8.7) Urinary Retention 5 (3.0) 23 (7.6) 22 (6.2)

Respiratory, Thoracic And MediastinalDisorders

18 (10.7) 30 (10.0) 31 (8.7)

Dyspnea 2 (1.2) 4 (1.3) 8 (2.2) Hiccups 4 (2.4) 4 (1.3) 1 (0.3) Hypoxia 4 (2.4) 3 (1.0) 3 (0.8)

Skin And Subcutaneous Tissue Disorders 24 (14.3) 63 (20.9) 84 (23.5) Hyperhidrosis 1 (0.6) 14 (4.7) 15 (4.2) Pruritus 10 (6.0) 45 (15.0) 55 (15.4) Pruritus Generalized 6 (3.6) 7 (2.3) 14 (3.9)

Vascular Disorders 16 (9.5) 30 (10.0) 44 (12.3) Hypertension 3 (1.8) 15 (5.0) 21 (5.9) Hypotension 11 (6.5) 8 (2.7) 19 (5.3)

6.2 Postmarketing ExperienceBecause adverse reactions reported during postmarketing are reported voluntarily from a population ofuncertain size, it is not always possible to reliably estimate their frequency or establish a causalrelationship to drug exposure.

These adverse reactions are consistent with those observed in clinical studies and most commonlyinvolve the following system organ classes (SOCs): Injury, Poisoning, and Procedural Complications(e.g., drug-drug interaction, procedural pain), Nervous System Disorders (e.g., palsy, seizure), GeneralDisorders And Administration Site Conditions (e.g., lack of efficacy, pain), Skin And SubcutaneousTissue Disorders (e.g., erythema, rash), and Cardiac Disorders (e.g., bradycardia, cardiac arrest).

7. DRUG INTERACTIONSThe toxic effects of local anesthetics are additive and their co-administration should be used withcaution including monitoring for neurologic and cardiovascular effects related to local anestheticsystemic toxicity [See Dosage and Administration (2.2), Warnings and Precautions (5.1), and Overdosage(10)]. Avoid additional use of local anesthetics within 96 hours following administration of EXPAREL.

Bupivacaine

Bupivacaine HCl administered together with EXPAREL may impact the pharmacokinetic and/orphysicochemical properties of EXPAREL, and this effect is concentration dependent. Therefore,bupivacaine HCl and EXPAREL may be administered simultaneously in the same syringe, andbupivacaine HCl may be injected immediately before EXPAREL as long as the ratio of the milligramdose of bupivacaine HCl solution to EXPAREL does not exceed 1:2.

Non-Bupivacaine Local Anesthetics

EXPAREL should not be admixed with local anesthetics other than bupivacaine. Non-bupivacaine basedlocal anesthetics, including lidocaine, may cause an immediate release of bupivacaine from EXPARELif administered together locally. The administration of EXPAREL may follow the administration oflidocaine after a delay of 20 minutes or more. There are no data to support administration of other localanesthetics prior to administration of EXPAREL.

Other than bupivacaine as noted above, EXPAREL should not be admixed with other drugs prior toadministration.

Water and Hypotonic Agents

Do not dilute EXPAREL with water or other hypotonic agents, as it will result in disruption of theliposomal particles.

8. USE IN SPECIFIC POPULATIONS

8.1 PregnancyRisk Summary

There are no studies conducted with EXPAREL in pregnant women. In animal reproduction studies,embryo-fetal deaths were observed with subcutaneous administration of bupivacaine to rabbits duringorganogenesis at a dose equivalent to 1.6 times the maximum recommended human dose (MRHD) of 266mg. Subcutaneous administration of bupivacaine to rats from implantation through weaning produceddecreased pup survival at a dose equivalent to 1.5 times the MRHD [see Data]. Based on animal data,advise pregnant women of the potential risks to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown.However, the background risk in the U.S. general population of major birth defects is 2-4% and ofmiscarriage is 15-20% of clinically recognized pregnancies.

Clinical Considerations

Labor or Delivery

Bupivacaine is contraindicated for obstetrical paracervical block anesthesia. While EXPAREL has notbeen studied with this technique, the use of bupivacaine for obstetrical paracervical block anesthesiahas resulted in fetal bradycardia and death.

Bupivacaine can rapidly cross the placenta, and when used for epidural, caudal, or pudendal blockanesthesia, can cause varying degrees of maternal, fetal, and neonatal toxicity [See ClinicalPharmacology (12.3)]. The incidence and degree of toxicity depend upon the procedure performed, thetype, and amount of drug used, and the technique of drug administration. Adverse reactions in theparturient, fetus, and neonate involve alterations of the central nervous system, peripheral vascular tone,and cardiac function.

Data

Animal Data

Bupivacaine hydrochloride was administered subcutaneously to rats and rabbits during the period oforganogenesis (implantation to closure of the hard plate). Rat doses were 4.4, 13.3, and 40 mg/kg/day(equivalent to 0.2, 0.5 and 1.5 times the MRHD, respectively, based on the BSA comparisons and a 60kg human weight) and rabbit doses were 1.3, 5.8, and 22.2 mg/kg/day (equivalent to 0.1, 0.4 and 1.6 timesthe MRHD, respectively, based on the BSA comparisons and a 60 kg human weight). No embryo-fetaleffects were observed in rats at the doses tested with the high dose causing increased maternal lethality.

An increase in embryo-fetal deaths was observed in rabbits at the high dose in the absence of maternaltoxicity.

Decreased pup survival was noted at 1.5 times the MRHD in a rat pre- and post-natal development studywhen pregnant animals were administered subcutaneous doses of 4.4, 13.3, and 40 mg/kg/daybupivacaine (equivalent to 0.2, 0.5 and 1.5 times the MRHD, respectively, based on the BSAcomparisons and a 60 kg human weight) from implantation through weaning (during pregnancy andlactation).

8.2 LactationRisk Summary

Limited published literature reports that bupivacaine and its metabolite, pipecoloxylidide, are present inhuman milk at low levels. There is no available information on effects of the drug in the breastfed infantor effects of the drug on milk production. The developmental and health benefits of breastfeedingshould be considered along with the mother’s clinical need for EXPAREL and any potential adverseeffects on the breastfed infant from EXPAREL or from the underlying maternal condition.

8.4 Pediatric UseSafety and effectiveness in pediatric patients have not been established.

8.5 Geriatric UseOf the total number of patients in the EXPAREL local infiltration clinical studies (N=823), 171 patientswere greater than or equal to 65 years of age and 47 patients were greater than or equal to 75 years ofage. Of the total number of patients in the EXPAREL nerve block clinical studies (N=531), 241 patientswere greater than or equal to 65 years of age and 60 patients were greater than or equal to 75 years ofage. No overall differences in safety or effectiveness were observed between these patients andyounger patients. Clinical experience with EXPAREL has not identified differences in efficacy orsafety between elderly and younger patients, but greater sensitivity of some older individuals cannot beruled out.

In clinical studies, differences in various pharmacokinetic parameters have been observed betweenelderly and younger patients. Bupivacaine is known to be substantially excreted by the kidney, and therisk of toxic reactions to bupivacaine may be greater in patients with impaired renal function. Becauseelderly patients are more likely to have decreased renal function, this should be considered whenperforming dose selection of EXPAREL.

8.6 Hepatic ImpairmentAmide-type local anesthetics, such as bupivacaine, are metabolized by the liver. Patients with severehepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater riskof developing toxic plasma concentrations, and potentially local anesthetic systemic toxicity.Therefore, consider increased monitoring for local anesthetic systemic toxicity in subjects withmoderate to severe hepatic disease.

8.7 Renal ImpairmentBupivacaine is known to be substantially excreted by the kidney, and the risk of toxic reactions to thisdrug may be greater in patients with impaired renal function. This should be considered whenperforming dose selection of EXPAREL.

10. OVERDOSAGEClinical Presentation

Acute emergencies from local anesthetics are generally related to high plasma concentrationsencountered during therapeutic use of local anesthetics or to unintended intravascular injection of localanesthetic solution [See Warnings and Precautions (5) and Adverse Reactions (6)].

Signs and symptoms of overdose include CNS symptoms (perioral paresthesia, dizziness, dysarthria,confusion, mental obtundation, sensory and visual disturbances, and eventually convulsions) and

cardiovascular effects (that range from hypertension and tachycardia to myocardial depression,hypotension, bradycardia, and asystole).

Plasma levels of bupivacaine associated with toxicity can vary. Although concentrations of 2,500 to4,000 ng/mL have been reported to elicit early subjective CNS symptoms of bupivacaine toxicity,symptoms of toxicity have been reported at levels as low as 800 ng/mL.

Management of Local Anesthetic Overdose

At the first sign of change, oxygen should be administered.

The first step in the management of convulsions, as well as underventilation or apnea, consists ofimmediate attention to the maintenance of a patent airway and assisted or controlled ventilation withoxygen and a delivery system capable of permitting immediate positive airway pressure by mask.Immediately after the institution of these ventilatory measures, the adequacy of the circulation should beevaluated, keeping in mind that drugs used to treat convulsions sometimes depress the circulation whenadministered intravenously. Should convulsions persist despite adequate respiratory support, and if thestatus of the circulation permits, small increments of an ultra-short acting barbiturate (such as thiopentalor thiamylal) or a benzodiazepine (such as diazepam) may be administered intravenously. The clinicianshould be familiar, prior to the use of anesthetics, with these anticonvulsant drugs. Supportive treatmentof circulatory depression may require administration of intravenous fluids and, when appropriate, avasopressor dictated by the clinical situation (such as ephedrine to enhance myocardial contractileforce).

If not treated immediately, both convulsions and cardiovascular depression can result in hypoxia,acidosis, bradycardia, arrhythmias, and cardiac arrest. If cardiac arrest should occur, standardcardiopulmonary resuscitative measures should be instituted.

Endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated, afterinitial administration of oxygen by mask, if difficulty is encountered in the maintenance of a patentairway or if prolonged ventilatory support (assisted or controlled) is indicated.

11. DESCRIPTIONEXPAREL is a sterile, non-pyrogenic white to off-white preservative-free aqueous suspension ofmultivesicular liposomes (DepoFoam drug delivery system) containing bupivacaine. Bupivacaine ispresent at a concentration of 13.3 mg/mL. After injection of EXPAREL, bupivacaine is released fromthe multivesicular liposomes over a period of time.

Active Ingredient

Bupivacaine is related chemically and pharmacologically to the amide-type local anesthetics. It is ahomologue of mepivacaine and is related chemically to lidocaine. All three of these anesthetics containan amide linkage between the aromatic nucleus and the amino, or piperidine group. They differ in thisrespect from the procaine-type local anesthetics, which have an ester linkage. Chemically, bupivacaineis 1-butyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide with a molecular weight of 288.4.Bupivacaine has the following structural formula:

Lipid Formulation

The median diameter of the liposome particles ranges from 24 to 31 μm. The liposomes are suspendedin a 0.9% sodium chloride solution. Each vial contains bupivacaine at a nominal concentration of 13.3mg/mL. Inactive ingredients and their nominal concentrations are: cholesterol, 4.7 mg/mL; 1, 2-dipalmitoyl-sn-glycero-3 phospho-rac-(1-glycerol) (DPPG), 0.9 mg/mL; tricaprylin, 2.0 mg/mL; and 1,2-dierucoylphosphatidylcholine (DEPC), 8.2 mg/mL. The pH of EXPAREL is in the range of 5.8 to 7.4.

®

Liposomal encapsulation or incorporation in a lipid complex can substantially affect a drug’s functionalproperties relative to those of the unencapsulated or nonlipid-associated drug. In addition, differentliposomal or lipid-complexed products with a common active ingredient may vary from one another inthe chemical composition and physical form of the lipid component. Such differences may affectfunctional properties of these drug products. Do not substitute.

12. CLINICAL PHARMACOLOGY

12.1 Mechanism of ActionLocal anesthetics block the generation and the conduction of nerve impulses presumably by increasingthe threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, andby reducing the rate of rise of the action potential. In general, the progression of anesthesia is related tothe diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, the order of lossof nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletalmuscle tone.

12.2 PharmacodynamicsSystemic absorption of local anesthetics produces effects on the cardiovascular and central nervoussystems. At blood concentrations achieved with normal therapeutic doses, changes in cardiacconduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal.However, toxic blood concentrations depress cardiac conductivity and excitability, which may lead toatrioventricular block, ventricular arrhythmias, and cardiac arrest, sometimes resulting in fatalities. Inaddition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreasedcardiac output and arterial blood pressure. Clinical reports and animal research suggest that thesecardiovascular changes are more likely to occur after accidental intravascular injection of bupivacaine.

Following systemic absorption, local anesthetics can produce central nervous system stimulation,depression, or both. Apparent central stimulation is manifested as restlessness, tremors, and shiveringprogressing to convulsions, followed by depression and coma progressing ultimately to respiratoryarrest. However, the local anesthetics have a primary depressant effect on the medulla and on highercenters. The depressed stage may occur without a prior excited state.

12.3 PharmacokineticsAdministration of EXPAREL results in systemic plasma levels of bupivacaine which can persist for 96hours after local infiltration and 120 hours after interscalene brachial plexus nerve block. [See Warningsand Precautions (5.2)]. In general, peripheral nerve blocks have shown systemic plasma levels ofbupivacaine for extended duration when compared to local infiltration. Systemic plasma levels ofbupivacaine following administration of EXPAREL are not correlated with local efficacy.

Absorption

The rate of systemic absorption of bupivacaine is dependent upon the total dose of drug administered,the route of administration, and the vascularity of the administration site.

Pharmacokinetic parameters of EXPAREL after local infiltration and following an interscalene brachialplexus nerve block were evaluated following surgical procedures. Descriptive statistics ofpharmacokinetic parameters of representative EXPAREL doses in each study are provided in Table 3.

Table 3: Summary of Pharmacokinetic Parameters for Bupivacaine after Adminis tration of Single Doses ofEXPAREL via Local Infiltration and Interscalene Brachial Plexus Nerve Block

Parameters

Surgical Site Adminis tration via LocalInfiltration

Interscalene Brachial PlexusNerve Block

Bunionectomy 106 mg (8 mL)

Hemorrhoidectomy 266 mg (20 mL)

Total Shoulder Arthroplas ty 133 mg (10 mL)

(N=26) (N=25) (N=12)C (ng/mL) 166 (92.7) 867 (353) 207 (137)T (h) 2 (0.5-24) 0.5 (0.25-36) 48 (3-74)

maxmax

Note: Arithmetic mean (standard deviation) except T where it is median (range).

AUC (h×ng/mL) 5864 (2038) 16,867 (7868) 11484 (8615)AUC (h×ng/mL) 7105 (2283) 18,289 (7569) 11590 (8603)t (h) 34 (17) 24 (39) 11 (5)

Distribution

After bupivacaine has been released from EXPAREL and is absorbed systemically, bupivacainedistribution is expected to be the same as for any bupivacaine HCl solution formulation.

Local anesthetics including bupivacaine are distributed to some extent to all body tissues, with highconcentrations found in highly perfused organs such as the liver, lungs, heart, and brain.

Local anesthetics including bupivacaine appear to cross the placenta by passive diffusion. The rate anddegree of diffusion is governed by (1) the degree of plasma protein binding, (2) the degree ofionization, and (3) the degree of lipid solubility. Fetal/maternal ratios of local anesthetics appear to beinversely related to the degree of plasma protein binding, because only the free, unbound drug isavailable for placental transfer. Bupivacaine with a high protein binding capacity (95%) has a lowfetal/maternal ratio (0.2 to 0.4). The extent of placental transfer is also determined by the degree ofionization and lipid solubility of the drug. Lipid soluble, non-ionized drugs such as bupivacaine readilyenter the fetal blood from the maternal circulation.

Elimination

Metabolism

Amide-type local anesthetics, such as bupivacaine, are metabolized primarily in the liver viaconjugation with glucuronic acid. Pipecoloxylidide (PPX) is the major metabolite of bupivacaine;approximately 5% of bupivacaine is converted to PPX. Elimination of drug depends largely upon theavailability of plasma protein binding sites in the circulation to carry it to the liver where it ismetabolized.

Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presenceof hepatic disease. Patients with hepatic disease, especially those with severe hepatic disease, may bemore susceptible to the potential toxicities of the amide-type local anesthetics.

Excretion

After bupivacaine has been released from EXPAREL and is absorbed systemically, bupivacaineexcretion is expected to be the same as for other bupivacaine formulations.

The kidney is the main excretory organ for most local anesthetics and their metabolites. Only 6% ofbupivacaine is excreted unchanged in the urine.

Urinary excretion is affected by urinary perfusion and factors affecting urinary pH. Acidifying the urinehastens the renal elimination of local anesthetics. Various pharmacokinetic parameters of the localanesthetics can be significantly altered by the presence of renal disease, factors affecting urinary pH,and renal blood flow.

Specific Populations

Hepatic Impairment

Because amide-type local anesthetics, such as bupivacaine, are metabolized by the liver, the effects ofdecreased hepatic function on bupivacaine pharmacokinetics following administration of EXPARELwere studied in patients with moderate hepatic impairment. Consistent with the hepatic clearance ofbupivacaine, mean plasma concentrations were higher in patients with moderate hepatic impairment thanin the healthy control volunteers with approximately 1.5- and 1.6-fold increases in the mean values forC and the area under the curve (AUC), respectively. [See Warnings and Precautions (5.1) and Use inSpecific Populations (8.6)].

13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenes is , Mutagenes is , Impairment of Fertility

max

(0-t)(inf)

½

max

Carcinogenesis

Long-term studies in animals to evaluate the carcinogenic potential of bupivacaine have not beenconducted.

Mutagenesis

The mutagenic potential of bupivacaine has not been determined.

Impairment of Fertility

The effect of bupivacaine on fertility has not been determined.

14. CLINICAL STUDIES

14.1 Studies Confirming EfficacyThe efficacy of EXPAREL compared to placebo was demonstrated in three multicenter, randomized,double-blinded clinical studies. For local analgesia via infiltration, one study evaluated the treatment inpatients undergoing bunionectomy; the other study evaluated the treatment in patients undergoinghemorrhoidectomy. For regional analgesia, one study evaluated the use of EXPAREL as a brachialplexus nerve block via interscalene or supraclavicular approach in patients undergoing total shoulderarthroplasty (TSA) or rotator cuff repair (RCR), however, only two subjects had nerve blocks via thesupraclavicular approach. Three additional studies did not provide sufficient efficacy and/or safety datato support a nerve block indication: two studies evaluated the use of EXPAREL via femoral block inpatients undergoing total knee arthroplasty (TKA), and one study evaluated the use of EXPAREL viaintercostal nerve block for patients undergoing posterolateral thoracotomy.

Study 1: Infiltration for Bunionectomy

A multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial(NCT00890682) evaluated the safety and efficacy of 106 mg (8 mL) EXPAREL in 193 patientsundergoing bunionectomy. The mean age was 43 years (range 18 to 72).

Study medication was administered directly into the site at the conclusion of the surgery, prior toclosure. There was an infiltration of 7 mL of EXPAREL into the tissues surrounding the osteotomy and1 mL into the subcutaneous tissue.

Pain intensity was rated by the patients on a 0 to 10 numeric rating scale (NRS) out to 72 hours.Postoperatively, patients were allowed rescue medication (5 mg oxycodone/325 mg acetaminophenorally every 4 to 6 hours as needed) or, if that was insufficient within the first 24 hours, ketorolac (15to 30 mg IV). The primary outcome measure was the area under the curve (AUC) of the NRS painintensity scores (cumulative pain scores) collected over the first 24-hour period. There was asignificant treatment effect for EXPAREL compared to placebo. EXPAREL demonstrated a significantreduction in pain intensity compared to placebo for up to 24 hours. There was no significant differencein the amount of morphine equivalents used through 72 hours post-surgery, 43 mg versus 42 mg forplacebo and EXPAREL, respectively. In addition, there was not a significant difference in thepercentage of patients that used ketorolac, 43% versus 31% for placebo and EXPAREL, respectively.

Study 2: Infiltration for Hemorrhoidectomy

A multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial(NCT00890721) evaluated the safety and efficacy of 266 mg (20 mL) EXPAREL in 189 patientsundergoing hemorrhoidectomy. The mean age was 48 years (range 18 to 86).

Study medication was administered directly into the site (greater than or equal to 3 cm) at the conclusionof the surgery. Dilution of 20 mL of EXPAREL with 10 mL of saline, for a total of 30 mL, was dividedinto six 5-mL aliquots. A field block was performed by visualizing the anal sphincter as a clock face andslowly infiltrating one aliquot to each of the even numbers.

Pain intensity was rated by the patients on a 0 to 10 NRS at multiple time points up to 72 hours.Postoperatively, patients were allowed rescue medication (morphine sulfate 10 mg intramuscular every4 hours as needed).

The primary outcome measure was the AUC of the NRS pain intensity scores (cumulative pain scores)collected over the first 72-hour period.

There was a significant treatment effect for EXPAREL compared to placebo. See Figure 1 for the meanpain intensity over time for the EXPAREL and placebo treatment groups for the 72-hour efficacyperiod.

Figure 1. Mean Pain Intens ity versus Time plot for hemorrhoidectomy s tudy (C-316)

There were statistically significant, but small differences in the amount of opioid rescue analgesia usedacross the treatment groups, the clinical benefit of which has not been established. The median time torescue analgesic use was 15 hours for patients treated with EXPAREL and one hour for patients treatedwith placebo. Twenty-eight percent of patients treated with EXPAREL required no rescue medication at72 hours compared to 10% treated with placebo. For those patients who did require rescue medication,the mean amount of morphine sulfate intramuscular injections used over 72 hours was 22 mg for patientstreated with EXPAREL and 29 mg for patients treated with placebo.

Study 3: Interscalene Brachial Plexus Nerve Block for Total Shoulder Arthroplasty or Rotator CuffRepair

A multicenter, randomized, double-blind, placebo-controlled study (NCT02713230) was conducted in156 patients undergoing primary unilateral total shoulder arthroplasty or rotator cuff repair with generalanesthesia. The mean age was 61 years (range 33 to 80). Prior to the surgical procedure, patientsreceived 10 mL of EXPAREL (133 mg) expanded with normal saline to 20 mL as a brachial plexusnerve block via interscalene or supraclavicular approach with ultrasound guidance. Only two patientsreceived nerve block with EXPAREL by supraclavicular approach. Postsurgically, patients wereadministered acetaminophen/paracetamol up to 1000 mg PO or IV every 8 hours (q8h) unlesscontraindicated. Patients were allowed opioid rescue medication administered initially as oralimmediate-release oxycodone (initiating at 5-10 mg every 4 hours or as needed). If a patient could nottolerate oral medication, IV morphine (2.5-5 mg) or hydromorphone (0.5-1 mg) could be administeredevery 4 hours or as needed.

In this study, there was a statistically significant treatment effect for EXPAREL compared to placebo incumulative pain scores through 48 hours as measured by the AUC of the visual analog scale (VAS)pain intensity scores. There were statistically significant, but small differences in the amount of opioidconsumption through 48 hours, the clinical benefit of which has not been demonstrated For thosepatients who required rescue medication, the mean amount of morphine-equivalent opioid rescue usedover 48 hours was 12 mg for patients treated with EXPAREL and 54 mg for patients treated withplacebo and 23 mg with EXPAREL vs. 70 mg for placebo over 72 hours.

Although at 48 hours, 9 subjects (13%) in the EXPAREL group remained opioid-free compared to 1subject (1%) in the placebo group, a difference which was statistically significant, at 72 hours, therewere 4 (6%) subjects in the EXPAREL group who remained opioid-free compared to 1 (1%) subject inthe placebo group, a difference that is not statistically significant.

14.2 Studies That Do Not Support an Indication in Nerve BlockStudies 4 and 5: Femoral Nerve Block in Total Knee Arthroplasty

EXPAREL was administered via a femoral nerve block in two placebo-controlled studies. The resultsof these studies did not support a femoral nerve block indication due to inadequate safety data (Study 4and Study 5) or due to inadequate efficacy findings (Study 5). In addition, patient falls were reportedonly in the EXPAREL treatment groups and none was reported in placebo groups.

Study 4

Study 4, a multicenter, randomized, double-blind, parallel-group, placebo-controlled study(NCT01683071), was conducted in 196 patients undergoing primary unilateral total knee arthroplasty(TKA) under general or spinal anesthesia. The mean age was 65 years (range 42 to 88). Prior to thesurgical procedure, 20 mL of EXPAREL (266 mg) was administered as a femoral nerve block withultrasound guidance. Postsurgically, patients were allowed opioid rescue medication administeredinitially by intravenous injection of hydromorphone and subsequently by a patient-controlled analgesia(PCA) pump containing morphine or hydromorphone only. Once patients were tolerating oralmedication, oral immediate-release oxycodone was administered on an as-needed basis (but not morethan 10 mg every 4 hours) or, if that was insufficient, a third rescue of bupivacaine HCl (0.125%, 1.25mg/mL) was administered at a rate of 8 mL per hour via the previously placed femoral nerve catheter.

In this study, there was a statistically significant treatment effect for EXPAREL compared to placebo incumulative pain scores through 72 hours as measured by the AUC of the NRS pain (at rest) intensityscores.

There was a statistically significant, although small decrease in opioid consumption for the EXPARELtreatment group compared to the placebo group, the clinical benefit of which has not been established.All patients in both the EXPAREL and placebo treatment groups required opioid rescue medicationduring the first 72 hours. The mean amount of opioid rescue used over 72 hours was 76 mg for patientstreated with EXPAREL and 103 mg for patients treated with placebo.

The study was inadequate to fully characterize the safety of EXPAREL when used for femoral nerveblock due to patient falls, which occurred only in the EXPAREL-treated patients and not the placebo-treated patients.

Study 5

Study 5, a multicenter, randomized, double-blind, parallel-group, placebo-controlled study(NCT02713178), was conducted in 230 patients undergoing primary unilateral total knee arthroplasty(TKA) under general or spinal anesthesia. The mean age was 65 years (range 39 to 89). Prior to thesurgical procedure, either 20 mL of EXPAREL (266 mg) or 10 mL of EXPAREL (133 mg) plus 10 mLof normal saline was administered as a femoral nerve block with ultrasound guidance. In addition tostudy drug, 8 mL of bupivacaine HCl (0.5%) diluted with 8 mL of normal saline was administered by thesurgeon as a periarticular infiltration to the posterior capsule (8 mL each behind the medial and lateralcondyles) before placement of the prosthesis. Postsurgically, patients were allowed opioid rescuemedication consisting of oral immediate-release oxycodone (initiated at 5 to 10 mg every 4 hours or asneeded). If a subject could not tolerate oral medication, IV morphine (2.5 to 5 mg) or hydromorphone(0.5 to 1 mg) was permitted every 4 hours or as needed. Patient-controlled analgesia was not permitted.No other analgesic agents, including NSAIDs, were permitted through 108 hours. However, to reflectthe current standard of care of postsurgical multimodal therapy, all subjects received cyclobenzaprine(a single dose of 10 mg orally or as needed) and acetaminophen/paracetamol (up to 1000 mg orally orIV every 8 hours for a maximum total daily dose of 3000 mg) postsurgically.

In this study there were no statistically significant treatment effects for the EXPAREL group comparedto the placebo group in cumulative pain intensity scores or total opioid consumption. All patients in theEXPAREL and placebo treatment groups required opioid rescue medication over 72 hours. The meanamount of opioid rescue used over 72 hours was 69 mg for patients treated with EXPAREL 133 mg; 74mg for patients treated with EXPAREL 266 mg, and 81 mg for patients treated with placebo. The medianT of bupivacaine observed in this study was 72 h with a range of 2.5 h to 108 h. Similarly to Study 4,patient falls only occurred in the EXPAREL-treated patients and not the placebo-treated patients.

Study 6: Intercostal Nerve Block for Posterolateral Thoracotomy

max

A multicenter, randomized, double-blind, placebo-controlled study was conducted in 191 patientsundergoing posterolateral thoracotomy under general anesthesia (NCT01802411). The mean age was58 years (range 18 to 82).

After the surgical procedure was completed but prior to the surgical site closure, 20 mL of EXPARELwas administered by the surgeon as an intercostal nerve block divided into three equal doses in threesyringes of approximately 88 mg in 6.6 mL volume per nerve, and administered to each of three nervesegments (index nerve, nerve above, and nerve below). Postsurgically, patients were allowed opioidrescue medication administered initially by intravenous fentanyl 100 mcg, which was to be administeredonce via bolus only. For the US sites, the second rescue medication was to be PCA-administeredmorphine or hydromorphone. For the European sites, the second rescue medication was to beintramuscular administered morphine up to10 mg every 4 hours. At all sites, once a subject wastolerating oral medication, oral immediate-release oxycodone was administered (but not more than 10mg every 4 hours). Subjects who did not achieve adequate pain relief with this regimen were to bewithdrawn from the study and followed for safety only.

In this study there were no statistically significant treatment effects for EXPAREL 266 mg compared toplacebo in cumulative pain intensity scores or total opioid consumption. Four percent of patients treatedwith EXPAREL required no rescue medication at 72 hours compared to 1% treated with placebo. Forthose patients who did require rescue medication, the mean amount of opioid rescue used over 72 hourswas 71 mg for patients treated with EXPAREL and 71 mg for patients treated with placebo. The medianT of bupivacaine observed in this study was 1 h with a range of 0.5 h to 50 h.

16. HOW SUPPLIED/STORAGE AND HANDLINGEXPAREL (bupivacaine liposome injectable suspension) is a white to off-white milky aqueoussuspension that is available in the following single-dose vials.

StorageStore EXPAREL vials refrigerated between 2°C to 8°C (36°F to 46°F). EXPAREL may be held at acontrolled room temperature of 20°C to 25°C (68°F to 77°F) for up to 30 days in sealed, intact(unopened) vials. Do not re-refrigerate vials.

Do not freeze or expose EXPAREL to high temperatures (greater than 40°C or 104°F) for an extendedperiod. Do not administer EXPAREL if it is suspected of having been frozen or exposed to hightemperatures. Do not use the vial if the stopper is bulging.

HandlingInvert vials of EXPAREL to re-suspend the particles immediately prior to withdrawal from the vial.Multiple inversions may be necessary to re-suspend the particles if the contents of the vial havesettled.Visually inspect vials for particulate matter and discoloration before use.Do not filter.Do not heat before use.Do not autoclave.Following withdrawal from the vial, store EXPAREL at controlled room temperature of 20°C to25°C (68°F to 77°F) for up to 4 hours prior to administration.Discard any unused portion in an appropriate manner.

17. PATIENT COUNSELING INFORMATIONInform patients in advance that EXPAREL can cause temporary loss of sensation or motor activity thatmay last for up to 5 days.

max

266 mg/20 mL (13.3 mg/mL) single-dose vial, (NDC 65250-266-20) packaged in cartons of 10(NDC 65250-266-09) and cartons of 4 (NDC 65250-266-04)

133 mg/10 mL (13.3 mg/mL) single-dose vial, (NDC 65250-133-10) packaged in cartons of 10(NDC-65250-133-09) and cartons of 4 (NDC 65250-133-04)

Pacira Pharmaceuticals, Inc.

San Diego, CA 92121 USA

Patent Numbers:

6,132,766

5,766,627

5,891,467

8,182,835

Trademark of Pacira Pharmaceuticals, Inc.

For additional information call 1-855-RX-EXPAREL (1-855-793-9727) or visit www.EXPAREL.com

Package Label - 10 mL Vial Label

Package Label - 10 mL 10-count Carton Label

Package Label - 10 mL 4-count Carton Label

Package Label - 20 mL Vial Label

Package Label - 20 mL 10-count Carton Label

Package Label - 20 mL 4-count Carton Label

EXPAREL bupivacaine injection, suspension, liposomal

Product InformationProduct T ype HUMAN PRESCRIPTION DRUG Ite m Code (Source ) NDC:6 5250 -133

Route of Adminis tration INFILTRATION

Active Ingredient/Active Moiety

Ingredient Name Basis o f Strength StrengthBUPIVACAINE (UNII: Y8 33539 4RO) (BUPIVACAINE - UNII:Y8 33539 4RO) BUPIVACAINE 13.3 mg in 1 mL

Packaging# Item Code Package Description Marketing Start Date Marketing End Date1 NDC:6 5250 -133-0 9 10 in 1 CARTON 0 9 /0 2/20 16

1 NDC:6 5250 -133-10 10 mL in 1 VIAL; Type 0 : No t a Co mbinatio n Pro duct

2 NDC:6 5250 -133-0 4 4 in 1 CARTON 0 9 /0 2/20 16

2 NDC:6 5250 -133-10 10 mL in 1 VIAL; Type 0 : No t a Co mbinatio n Pro duct

Marketing InformationMarke ting Cate gory Application Numbe r or Monograph Citation Marke ting Start Date Marke ting End Date

NDA NDA0 2249 6 0 1/0 1/20 16

EXPAREL bupivacaine injection, suspension, liposomal

Product InformationProduct T ype HUMAN PRESCRIPTION DRUG Ite m Code (Source ) NDC:6 5250 -26 6

Route of Adminis tration INFILTRATION

Active Ingredient/Active MoietyIngredient Name Basis o f Strength Strength

BUPIVACAINE (UNII: Y8 33539 4RO) (BUPIVACAINE - UNII:Y8 33539 4RO) BUPIVACAINE 13.3 mg in 1 mL

Packaging# Item Code Package Description Marketing Start Date Marketing End Date1 NDC:6 5250 -26 6 -0 9 10 in 1 CARTON 0 3/31/20 17

1 NDC:6 5250 -26 6 -20 20 mL in 1 VIAL; Type 0 : No t a Co mbinatio n Pro duct

2 NDC:6 5250 -26 6 -0 4 4 in 1 CARTON 0 9 /28 /20 16

2 NDC:6 5250 -26 6 -20 20 mL in 1 VIAL; Type 0 : No t a Co mbinatio n Pro duct

Marketing InformationMarke ting Cate gory Application Numbe r or Monograph Citation Marke ting Start Date Marke ting End Date

NDA NDA0 2249 6 0 1/0 1/20 12

Labeler - Pacira Pharmaceuticals Inc. (783298615)

EstablishmentName Addre ss ID/FEI Bus ine ss Ope rations

Pacira Pharmaceutica ls Inc . 78 329 8 6 15 MANUFACTURE(6 5250 -133, 6 5250 -26 6 )

Pacira Pharmaceuticals Inc. Revised: 6/2018